[unreadable] [unreadable] The long-term goal of the proposed studies is to develop strategies that will reduce breast cancer incidence by optimizing vitamin A trafficking in the mammary gland. The naturally occurring active forms of vitamin A [all- trans- (ATRA) and 9-cis- (9-cRA) retinoic acid] have potent effects on proliferation and differentiation; however, because the effective doses produce systemic toxicities, their utilization in the context of cancer prevention is not practical. Because the mammary gland expresses the enzymatic machinery to produce ATRA and 9-cRA from dietary vitamin A, an alternative and potentially less toxic approach is to deliver precursor vitamin A compounds to mammary cells. However, little is known about vitamin A uptake or transport in mammary epithelial cells. In the proximal tubule cells of the kidney, endocytosis mediated by megalin, cubilin, and Disabled-2 (Dab2) is required for the uptake of the major circulating form of vitamin A (retinol). Megalin is also expressed in the absorptive epithelia of various extra renal sites, including the mammary gland. Moreover, we have recently detected cubilin and Dab2 in mammary epithelial cells and murine mammary gland. In the studies proposed here, we will test our central hypothesis that megalin, cubilin, and/or Dab2 are essential for the uptake and anti-proliferative effects of retinol in the mammary gland (Aims 1 and 2). A corollary to this hypothesis is that loss of megalin, cubilin, and/or Dab2 might lead to deregulation of vitamin A-mediated growth control. We believe that by understanding the uptake mechanisms of retinol, as well as the expression profile of megalin, cubilin, and Dab2 in the mammary gland (Aim 3), we will be better able to develop dietary strategies that utilize dietary vitamin A for the prevention of breast cancer. [unreadable] [unreadable] [unreadable]